Toshiyuki Mano

Differentiation of dys- and demyelination using diffusional anisotropy

We attempted differential diagnosis of dysmyelination and demyelination in childhood using magnetic resonance diffusion weighted imaging. Pelizaeus-Merzbacher disease, one of the dysmyelination disorders, demonstrated diffuse high intensity of the cerebral white matter on T2-weighted images, which demonstrated diffusional anisotropy on diffusion weighted images. On the other hand, high intensity lesions on T2-weighted images in Krabbe disease, one of the demyelination disorders, lost diffusional anisotropy. Another demyelination disorder, Alexander disease-related disorder, also lost its diffusional anisotropy. In contrast to relatively high signal of the lesions on diffusion-weighted images in Krabbe disease (high signal type), the lesions in Alexander disease-related disorder showed low signal on diffusion-weighted images (low signal type). These results suggest that diffusion-weighted images will be clinically useful to differentiate dysmyelination from demyelination; both of them demonstrate similar high intensity lesions of the white matter on T2-weighted images.

Mutational analysis of MECP2 in Japanese patients with atypical Rett syndrome

Rett syndrome (RTT) is one of the most common neurodevelopmental disorders in females. Recently, this disease was found to be linked with mutations in the methyl-CpG-binding protein 2 gene (MECP2) and various mutations have been reported. To explore the spectrum of phenotypes resulting from MECP2 mutations, we searched for mutations in the MECP2 of 20 Japanese patients who had more than five of the criteria necessary for RTT diagnosis proposed in 1988 (The Rett Syndrome Diagnostic Criteria Work Group, Ann Neurol 23 (1988) 425) and compared the phenotype between patients with and without mutation by giving a score to each diagnostic criterion. We found four missense mutations (T158M, R133C, Y120D, and R306C), two nonsense mutations (R168X and R270X), one frameshift (726delAAAG) mutation, and one polymorphism (A201V) in ten patients (50%). This included two novel mutations (726delAAAG and Y120D). All mutations were found in the highly conserved methyl-binding and transcription repression domains. Comparison of the mean total diagnostic criterion score of the groups with and without mutation did not reveal any statistically significantly difference (P=0.28). The only difference between the groups, which was of borderline significance (P=0.051), was the sum of the scores for diagnostic criteria 2 (apparently normal psychomotor development through the first 6 months) and 5 (loss of acquired purposeful hand skills between the ages of 6 and 30 months). From these results, it is suggested that the clinical phenotype of RTT is variable and it is important to investigate the MECP2 genotype for patients having more than five criteria and not only in those who exhibit all RTT diagnostic criteria. The diagnosis of RTT is clinically difficult before 3 years of age, especially in atypical cases, but molecular analysis of the MECP2 will assist diagnosis in some patients.

Remission of progressive multifocal leukoencephalopathy following highly active antiretroviral therapy in a patient with HIV infection.

Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease resulting from lytic infection of oligodendrocytes by the papovavirus JC (JCV). PML has also been recognized as an AIDS-defining illness. The incidence of PML has increased since 1987 and it occurs in up to 4% of patients with AIDS. To date, there is no treatment available for PML and it usually results in death within 3-6 months of diagnosis. However, there are some reports of remission of PML after antiretroviral therapy. We report a 12-year-old child with hemophilia B and developing AIDS with the onset of PML. With highly active antiretroviral therapy, PML subsided with an increase of CD4 count from 10 to 300/microl in spite of about 1.0 X 10(4) human immunodeficiency virus (HIV)-1-RNA copies. He has survived more than 1 year without specific therapy against JCV. Highly active antiretroviral therapy appears to have improved his prognosis in HIV-associated PML.

Pelizaeus-Merzbacher disease caused by a duplication-inverted triplication-duplication in chromosomal segments including the PLP1 region.

Pelizaeus-Merzbacher disease (PMD; MIM#312080) is a rare X-linked leukodystrophy presenting with motor developmental delay associated with spasticity and nystagmus. PMD is mainly caused by abnormalities in the proteolipid protein 1 gene (PLP1), most frequently due to duplications of chromosomal segments including PLP1. In this study, a 9-year-old male patient manifesting severe developmental delay and spasticity was analyzed for PLP1 alteration, and triplication of PLP1 was identified. Further examination revealed an underlying genomic organization, duplication-inverted triplication-duplication (DUP-TRP/INV-DUP), in which a triplicated segment was nested between 2 junctions. One of the 2 junctions was caused by inverted homologous regions, and the other was caused by non-homologous end-joining. PMD patients with PLP1 duplications usually show milder-classical forms of the disease compared with patients with PLP1 missense mutations manifesting severe connatal forms. The present patient showed severe phenotypic features that represent an intermediate form of PMD between classical and connatal forms. This is the first report of a patient with PLP1 triplication caused by a DUP-TRP/INV-DUP structure. This study adds additional evidence about the consequences of PLP1 triplication.

Diagnostic accuracy of blood and CSF lactate in identifying children with mitochondrial diseases affecting the central nervous system

OBJECTIVE To determine the diagnostic accuracy of blood and cerebrospinal fluid (CSF) lactate and pyruvate concentrations in identifying children with mitochondrial diseases (MD) affecting the central nervous system (CNS). METHODS We studied lactate and pyruvate concentrations in paired samples of blood and CSF collected concurrently from 17 patients with MD (Leigh encephalomyelopathy 10, MELAS 5, Pearson disease 1, PDH deficiency 1) and those from control patients (n=49). RESULTS Although blood and CSF variables (lactate, pyruvate concentrations and lactate/pyruvate ratio) were significantly higher in the mitochondrial group than in the control group, there was considerable overlap of individual values between these two groups. The maximum value of the area under the receiver operating characteristic curve (AUC) was observed for the CSF lactate concentration (0.994, optimal cut-off value 19.9 mg/dl, sensitivity 0.941 and specificity 1.00), followed by the CSF pyruvate level (0.983). There was an inverse relationship between blood lactate and lactate CSF/blood ratio. For blood lactate concentrations between 20 and 40 mg/dl, a significant difference was also noted in the lactate CSF/blood ratio between the two groups (AUC 1.0, optimal cut-off value 0.91, sensitivity 1.0 and specificity 1.0). CONCLUSIONS Our study suggests that that CSF lactate level>19.9 mg/dl is the most reliable variable for identifying patients with MD affecting the CNS. When blood lactate concentrations are marginally elevated (20-40 mg/dl), lactate CSF/blood ratio>0.91 may also provide diagnostic information.

Characteristic MR features of encephalitis caused by Epstein-Barr virus: a case report

Abstract An 8-year-old girl showed symptoms of encephalitis during acute Epstein-Barr virus (EBV) infection. The diagnosis of EB virus infection was made by changes in the titres of EB virus-specific antibody. Cranial MRI demonstrated abnormal low and high signal intensities in the striatal body (putamen and caudate nucleus) on T1-weighted and T2-weighted images, respectively, during the acute phase. These abnormal findings had almost completely resolved 1 month later. EBV infection should be considered when lesions are localised to the basal ganglia.

MR findings and neurologic manifestations in Lowe oculocerebrorenal syndrome

Two patients with oculocerebrorenal syndrome are described. Both had abnormal findings on electroencephalography and developed seizure episodes. Although Patient 2 manifested abnormal electroencephalographic findings at the age of 6 years, he did not develop seizures until the age of 9 years. Phenytoin was effective for controlling seizures in both patients. On magnetic resonance examination, there were two different types of lesions. The first lesion manifested high intensity on both T2- and proton density-weighted images, suggesting gliosis or demyelination. The second lesion manifested definitely low signals on both T1- and proton density-weighted images, implying a cystic lesion. However, these lesions on magnetic resonance examination were not correlated with the severity of clinical manifestations.

Intracranial lipoma of the quadrigeminal region associated with complex partial seizures.

Abstract A 7-year-old Japanese boy with an intracranial lipoma of the quadrigeminal region and complex partial seizures is reported. Among 28 published patients with lipoma originating in the quadrigeminal plate and ambient cistern, 6 suffered from seizures and 3 were mentally retarded. Our patients seizures were controlled with carbamazepine.

INTERSTITIAL DELETION OF 14Q, 46, XY, DEL (14) (Q24.3Q32.1) ASSOCIATED WITH STATUS NONEPILEPTIC MYOCLONIA AND DELAYED MYELINATION

A Japanese boy with interstitial deletion of the long arm of chromosome 14, including band 14q31, is described. The characteristic dysmorphic facial features, such as dolichocephaly, bushy eyebrows, horizontal narrow palpebral fissures, long philtrum, etc, and mental and motor developmental delay were observed. Other characteristic clinical manifestations were anuresis and status nonepileptic myoclonia. The finding of delayed myelination of the cerebral white matter was observed on magnetic resonance examination, suggesting that an unknown factor related to myelination in the central nervous system might be localized in band 14q31. (J Child Neurol 1999;14:756-758).

Proton magnetic resonance spectroscopy of Sjögren-Larsson syndrome heterozygotes.

A deficit of fatty alcohol:NAD+ oxidoreductase complex (FAO) activity has been detected in patients with the Sjögren‐Larsson syndrome (SLS). A moderate decrease in FAO activity has also been reported in heterozygote SLS subjects. Abnormal peaks were detected with proton magnetic resonance spectroscopy (1H‐MRS) in homozygote SLS subjects. The purpose of this study was to examine whether 1H‐MRS can be used to detect metabolic and/or pathological abnormalities in heterozygote SLS subjects. Four SLS heterozygotes were examined using 1H‐MRS. A moderate decrease in FAO activity was demonstrated in two of the four heterozygotes. Abnormal peaks were detected at 0.9 ppm in the spectrum from cerebral hemispheres of every heterozygote. 1H‐MRS was able to detect an abnormal accumulation of fatty alcohols and lipids, which is expected to increase due to an decrease in FAO activity or dysmyelination in heterozygote SLS subjects. Thus, 1H‐MRS is suggested to be a powerful tool in the screening of SLS heterozygotes. Magn Reson Med 45:1112–1115, 2001.